S-heterocyclic derivatives of phosphine or phosphite gold mercaptides

ABSTRACT

S-Heterocyclic derivatives of phosphine or phosphite gold mercaptides are prepared by reaction of an heterocyclic mercaptan compound with an appropriate phosphine or phosphite gold halide in the presence of alkali.

United States Patent Sutton et al.

[4 1 May 13, 1975 S-HETEROCYCLIC DERIVATIVES OF PHOSPHINE OR PHOSPHITEGOLD MERCAPTIDES Inventors: Blaine M. Sutton, Hatboro; Joseph Weinstock,Phoenixville, both of Pa.

SmithKline Corporation, Philadelphia, Pa.

Filed: Aug. 1, 1973 Appl. No.: 384,666

Assignee:

US. Cl. 260/299; 260/430; 424/200 Int. Cl.. C07d 91/32; C07d 85/44; C07d49/36 Field of Search 260/299 References Cited UNITED STATES PATENTS3/l970 Schroder et al. 260/299 3,755,329 8/1973 Vaughan 260/299 PrimaryExaminer-Richard J. Gallagher Attorney, Agent, or Firm-Janice E.Williams; Alan D. Lourie; William H. Edgerton [57] ABSTRACT 6 Claims, NoDrawings S-IIETEROCYCLIC DERIVATIVES OF PHOSPHINE OR PHOSPI-IITE GOLDMERCAPTIDES This invention relates to novel S-heterocyclic derivativesof phosphine or phosphite gold mercaptides which have usefulpharmacological activity. More specifically, the compounds of thisinvention have antiarthritic activity as measured by their ability toinhibit adjuvant-induced polyarthritis in rats.

The compounds of this invention are represented by the followingstructural formula:

in which:

R is lower alkyl, lower alkoxy, phenyl or phenoxy, with each alkyl oralkoxy having from one to three carbon atoms;

X is S, NH, NCH or O;

R and R are hydrogen or together form a 1,2-benzo radical; and

1;: indicates an optional double bond.

Preferred compounds of this invention are represented by Formula I whereR is lower alkyl. Also preferred are those compounds of Formula I wherethe heterocyclic moiety is 2-thiaz olinyl, 2-benzimidazolyl and2-benzoxazolyl.

The compounds of this invention are prepared by reaction of anheterocyclic mercaptan compound with an appropriate phosphine orphosphite gold(l) halide, preferably chloride, in the presence of alkalisuch assodium hydroxide in a solvent such as aqueous alcoholchloroformat about 25 for approximately 1 hour in a nitrogen atmosphere.

The phosphine or phosphite gold halides employed as starting materialsare prepared by reaction of a cold (10 to 5) solution of gold(l)chloride, prepared by mixing thiodiglycol and gold acid chloridetrihydrate in aqueous alcohol, with an appropriate phosphine or.

phosphite such as triethylphosphine. Other procedures which may beapplied to the preparation of these intermediates are found in J. Chem.Soc. 1828 (1937) and 1235 (1940) and Australian J. Chem. 19:547 (1966).

The anti-arthritic activity of the compounds of this invention ismeasured by their ability to inhibit adjuvant-induced polyarthritis inrats. The compounds of Formula I produce marked inhibition of thedevelopment of adjuvant arthritis in rats at daily oral doses as low asabout 20 mg. per kilogram of body weight. Of particular importance istheattainment of significant serum levels of gold following oraladministration of these doses.

Adjuvant arthritis in rats is produced by a single injection of 0.75 mg.of Mycobacterium butyricum suspended in white paraffin (NF) into ahindpaw (left footpad). The injected leg becomes inflamed and reaches amaximum volume in 3 to 5 days (primary lesion). The animals exhibit adecrease in body weight gain during this initial period. Adjuvantarthritis (secondary phase) occurs after a delay of approximately 10days and is characterized by inflammation of the noninjected sites(right hind leg), decrease in body weight gain and further increases inthe volume of the injected hind leg. The compounds of Formula Iadministered in the doses described above beginning on the day of ad- 5juvant injection and continuing for 17 days thereafter,

exclusive of days 4, 5, 11 and 12, protect the animals againstdevelopment of both primary and secondary lesions of adjuvant arthritis.

The compounds of this invention are administered in conventional dosageunit forms by incorporating an amount sufficient to produceanti-arthritic activity, without toxic effects, with a nontoxicpharmaceutical carrier according to accepted procedures. Preferably thedosage units will contain an S-heterocyclic derivative of a phosphine orphosphite gold mercaptide of Formula I in an amount of from about 0.5mg. to about 25 mg., preferably 0.5 mg. to 10 mg. calculated on goldcontent, per unit.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil,

olive oil, water and the like. Similarly, the carrier or dili uent caninclude any time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or an aqueous ornonaqueous liquid suspension.

The method of producing anti-arthritic activity in ac-' cordance withthis invention comprises administering internally to an animal organisman S-heterocyclic derivative of a phosphine or phosphite gold mercaptideof Formula I, usually combined with a pharmaceutical carrier, in anamount sufficient to produce antiarthritic activity without limitingside effects. The active medicament will be administered in a dosageunit, as described above, orally or parenterally, the oral route beingpreferred. Advantageously equal doses will be administered one or twotimes daily with the daily dosage regimen being from about 0.5 mg. toabout 50 mg., preferably 0.5 mg. to about 20 mg., calculated on goldcontent. When the method described above is carried out, anti-arthriticactivity is produced with a minimum of side effects.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to the desired end product.

The following examples illustrate the preparation of compounds of thisinvention and their incorporation into pharmaceutical compositions, andas such are not to be construed as limiting the invention set forth inthe claims appended hereto. Temperatures are in degrees Centigradeunless otherwise stated.

EXAMPLE 1 2-Thiazoliny1thio(triethylphosphine)gold A solution of 10.0 g.(0.08 mol.) of thiodiglycol in 25 ml. of ethanol was mixed with asolution of 15.76 g. (0.04 mol.) of gold acid chloride trihydrate in 75ml. of distilled water. When the bright orange-yellow solution wasalmost colorless, it was cooled to below and an equally cold solution of5.0 g. (0.0425 mol.) of triethylphosphine in 25 ml. of ethanol was addeddropwise to the stirred solution. After the addition was complete, thecooled mixture was stirred for 30 minutes. The solid that separated wasremoved by filtration and the filtrate was concentrated to about 30 ml.to yield a second crystal crop. The combined solid was washed with 2:1aqueous ethanol and recrystallized from ethanol by addition of water tothe cloud point to give chloro(triethylphosphine)gold, m.p. 85-86.

To a solution of 0.8 g. (0.02 mol.) ofsodium hydroxide in 20 ml. of 1:1aqueous ethanol was added a solution of 2.4 g. (0.02 mol.) of2-mercaptothiazoline in 20 ml. of 1:1 ethanol-chloroform followed by asolution of 7.0 g. (0.02 mol.) of chloro(triethylphosphine)gold in 40ml. of 1:1 ethanol-chloroform. The reaction mixture was stirred undernitrogen at 25 for 1 hour, then it was filtered and the filtrate wasevaporated to dryness. Chloroform was added to the residue and thesolution was again evaporated to dryness to give a thick yellow liquidwhich crystallized when triturated with acetone and cooled over dry iceto give the title compound, m.p. 70-7 1 (acetone-water).

EXAMPLE 2 2-Benzimidazolylthio(triethylphosphine )gold To a solution of0.4 g. (0.01 mol.) of sodium hydroxide in 20 ml. of 1:1 aqueous ethanolwas added 1.5 g. (0.01 mol.) of Z-mercaptobenzimidazole in 20 ml. ofethanol followed by 3.5 g. (0.1 mol.) of chloro(triethylphosphine)goldin 20 ml. of 1:1 chloroform-ethanol. The reaction mixture was stirredfor 1 hour at 25 under nitrogen, then it was filtered and the filtrateevaporated to dryness to give the title compound as a white solid, m.p.222-223 (ethanol).

EXAMPLE 3 2-Benzoxazolylthio(triethylphosphine )gold To a solution of0.6 g. (0.015 mol.) of sodium hydroxide in 20 ml. of 1:1 aqueous ethanolwas added 2.28 g. (0.015 mol.) of 2-mercaptobenzoxazole in 20 ml.ofethanol followed by 5.25 g. (0.015 mol.) ofchloro(triethylphosphine)-gold in 40 ml. of 1:1 ethanolchloroform. Thereaction mixture was stirred at 25 for l-hour under nitrogen, filteredand the filtrate was evaporated to dryness to give a residue which wasdissolved in methanol and treated with activated charcoal to give thetitle compound as white crystals, m.p. l00l02 (methanol).

EXAMPLE 4 A solution of 2.44 g. (0.02 mol.) of thiodiglycol in 15 ml. ofmethanol was mixed with a solution of 3.98 g. (0.01 mol.) of gold acidchloride trihydrate in 25 ml. of distilled water. When the orange-yellowsolution became almost colorless, it was cooled to 15 and an equallycold solution of 760 mg. (0.01 mol.) oftrimethylphosphine in ml. ofmethanol was added dropwise to the stirred solution. After the addition,the cooled mixture was stirred for 30 minutes, then the product wasfiltered off and the filtrate was concentrated in vacuo to give a secondcrystal crop. The combined solid material was washed with cold aqueousmethanol (2:1) and water to give chloro(trimethylphosphine)- gold, m.p.228229.

When an equivalent amount of chloro(trimethylphosphine)gold issubstituted in the procedure of Example 1 forchloro(triethylphosphine)gold, 2-thiazolinylthio(trimethylphosphine)gold is obtained.

In like manner, substitution of an equivalent amount ofchloro(trimethylphosphine)gold in the procedures of Examples 2 and 3 forchloro(triethylphosphine)gold gives2-benzimidazolylthio(trimethylphosphine)gold and2-benzoxazolylthio(trimethylphosphine)gold, respectively.

EXAMPLE 5 A mixture of 11.82 g. (0.03 mol.) of gold acid chloridetrihydrate and 1.9 g. (0.065 mol.) of thiodiglycol in m1. of aqueousethanol (3:2) was stirred until the color of auric gold disappeared. Thealmost colorless solution was cooled below 5 and an equally coldsolution of 5.6 g. (0.035 mol.) of triisopropylphosphine in 20 ml. ofethanol was added dropwise. The volume of the final reaction mixture wasincreased to 250 ml. with 1:1 aqueous ethanol in order to maintain afluid mixture. After addition the mixture was stirred in the cold for 45minutes. The solid was removed by filtration, washed with 1:2alcohol-water and water and dried (MgSO then redissolved by suspensionin ethanol and addition of sufficient methylene chloride to attainsolution. The cloudy solution was filtered from suspended gold and thefiltrate was concentrated to give chloro(triisopropylphosphine)gold aswhite crystals, m.p. 184l86.

Substitution of an equivalent amount ofchloro(triisopropylphosphine)gold in the procedure of Example 1 forchloro(triethylphosphine)gold gives 2-thiazolinylthio(triisopropylphosphine)gold.

Similarly, when an equivalent amount ofchloro(triisopropylphosphine)gold is substituted in the procedure ofExample 2 for chloro(triethylphosphine)gold, 2-benzimidazolylthio(triisopropylphosphine)gold is obtained.

In like manner, 2-benzoxazolylthio(triisopropylphosphine)gold isprepared by substitution of an equivalent amount ofchloro(triisopropylphosphine)gold in the procedure of Example 3 forchloro(triethylphosphine)- gold.

EXAMPLE 6 Gold acid chloride trihydrate (4.0 g; 0.01 mol.) was reducedto aurous chloride with 2.44 g. of thiodiglycol in 1:2 aqueous ethanol.After cooling the solution in an ice bath, a cold solution of 2.26 g.(0.01 mol.) of triphenylphosphine in a minimum amount of ethanol wasadded with stirring. The reaction mixture was stirredthiazolinylthio(triphenylphosphine)gold is obtained.

Likewise, 2-benzimidazolylthio(triphenylphosphine)-gold and 2benzoxazolylthio(triphenylphosphine)gold are obtained by substitution ofequivalent amounts of chloro(triphenylphosphine)gold in the proceduresof Examples 2 and 3, respectively, for chloro(t riethylphosphine)gold.

EXAMPLE 7 Gold acid chloride trihydrate (3.58 g.; 0.009 mol.) wasreduced to aurous chloride with 3.29 g. (0.027 mol.) of thiodiglycol in70 ml. of water saturated with sodium chloride. To the fresh solutionwas added 1.52 g. (0.009 mol.) of diethylphenylphosphine in 20 ml. ofethanol and the reaction mixture was stirred for 1 hour at 25 under anitrogen atmosphere. The reaction mixture was then extracted withchloroform and the extract was washed with water and dried (MgSOConcentration gave a residue which was chromatographed on silica gelwith benzene and chloroform to give chloro(diethylphenylphosphine)gold.

When an equivalent amount of chloro(diethylphenylphosphine)gold issubstituted in the procedure of Example l forchloro(triethylphosphine)gold, 2-thiazolinylthio(diethylphenylphosphine)gold is obtained.

Likewise, 2-benzimidazolylthio(diethylphenylphosphine(gold and2-benzoxazolylthio(diethylphenylphosphine)gold are obtained bysubstitution of equivalent amounts of chloro(diethylphenylphosphine)goldin the procedures of Examples 2 and 3, respectively, for chro(triethylphosphine)gold.

EXAMPLE 8 By following procedures outlined in J. Chem. Soc. 1828 (1937),iodo(trialkylphosphine)gold complexes are prepared, for example,iodo(triethylphosphine)- gold.

When an equivalent amount of iodo(triethylphosphine)gold is substitutedin the procedure of Example 1 for chl0ro(triethylphosphine)gold, 2-thiazolinylthio(triethylphosphine)gold is obtained.

Similarly, by following procedures outlined in J. Chem. Soc. 1235(1940), bromo(trialkylphosphine)- gold complexes are prepared, forexample, br0mo(triethylphosphine)gold.

Substitution of an equivalent amount of bromo(triethylphosphine)gold inthe procedure of Example 1 for chloro(triethylphosphine)gold also gives2- thiazolinylthio(triethylphosphine)gold.

By similar procedures, the other S-heterocyclic derivatives of phosphinegold mercaptides of Formula I may be prepared as described from theappropriate phosphine gold(l) iodides and bromides.

EXAMPLE 9 Gold acid chloride trihydrate (5.9 g.; 0.015 mol.) is reducedto aurous chloride with 3.7 g. (0.03 mol.) of thiodiglycol in 1:2aqueous ethanol. The solution is cooled to l0 and an equally coldsolution of 3.72 g. (0.02 mol.) of triethylphosphite in ml. of ethanolis added dropwise with stirring. The temperature is maintained at 1 0and stirring is continued for 30 minutes. The ethanol is removed fromthe reaction mixture under reduced pressure without heating and theaqueous residue is. then extracted with methylene chloride. The extractis dried and the solvent evaporated in vacuo. The crude product ispurified by chromatography on a silica gel column to givechloro(triethylphosphite)gold as an oil.

Substitution of an equivalent amount of chloro(triethylphosphite)gold inthe procedure of Example 1 for chloro(triethylphosphine)gold gives 2-thiazolinylthio(triethylphosphite)gold.

When an equivalent amount of chloro(triethylphosphite)gold issubstituted in the procedure of Example 2 forchloro(triethylphosphine)gold, 2benzimidazo1ylthio(triethylphosphite)gold is obtained.

Similarly, substitution of an equivalent amount ofchloro(triethylphosphine)gold in the procedure of Example 3 forchloro(triethylphosphine)gold gives 2-benzoxazolylthio(triethylphosphite)gold.

EXAMPLE 10 Gold acid chloride trihydrate (4.0 g.; 0.01 mol.) was reducedto aurous chloride with 2.44 g. of thiodiglycol in 1:2 aqueous methanol.The solution was cooled in an ice bath and a cold solution of 1.5 g. oftrimethyl' phosphite in 10 ml. of methanol was added dropwise withstirring under nitrogen. The reaction mixture was stirred for 30minutes, filtered and the solid was washed with cold aqueous methanoland dried. The product was dissolved in 5 ml. of chloroform and thissolution was diluted with 10 ml. of methanol and filtered throughcharcoal. The filtrate was concentrated under reduced pressure and theresidue was cooled and diluted with ice-water to precipitatechloro(trimethylphosphite)gold, m.p. 99100.

When an equivalent amount of chloro(trimethylphosphite)gold issubstituted in the procedures of Examples 1, 2 and 3 forchloro(triethylphosphine)gold,

2-thiazolinylthio(trimethylphosphite )gold, 2-benzimidazolylthio(trimethylphosphite gold and 2-benzoxazolylthio(trimethylphosphite )gold are obtained, respectively.

EXAMPLE I 1 When an equivalent amount of triphenylphosphite issubstituted in the procedure of Example 10 for trimethylphosphite,chloro(triphenylphosphite)g0ld is obtained.

Substitution of an equivalent amount of chloro(triphenylphosphite)goldin the procedure of Example 1 for chloro(triethylphosphine)gold gives 2thiazolinylthio(triphenylphosphite)gold.

In like manner, when an equivalent amount ofchloro(triphenylphosphite)gold is substituted in the procedures ofExamples 2 and 3 for chloro(triethylphosphine)gold2-benzimidazolylthio(triphenylphosphite)- gold are obtained.

EXAMPLE l2 Substitution of an equivalent amount of a mercaptoheterocycle listed below:

Z-mercaptobenzothiazole 2-mercaptol -methylimidazole 2-mercaptothiazoleZ-mercaptooxazole in the procedure of Example 1 for 2mercaptothiazolinegives the following S-heterocyclic derivatives of triethylphosphinegold:

2-benzothiazolylthio(triethylphosphine)gold 2-( l-methylimidazolyl)thio(triethylphosphine )gold 2-thiazolylthio(triethylphosphine gold2-oxazolylthio( triethylphosphine gold.

In like manner, the mercapto heterocycles listed above may be allowed toreact with the other phosphine or phosphite gold halides disclosedherein.

EXAMPLE 13 Ingredients Mg./Tablet 2-Benzoxaz0lylthio(triethyllphosphinc)gold C'alcium sulfate dihyclrate lSO Sucrose 25 Starch l Tale5 Stearic acid 3 The sucrose, calcium sulfate and 2- in which:

R is lower alkyl, lower alkoxy, phenyl or phenoxy, with each alkyl oralkoxy having from one to three carbon atoms;

x is 5, NH, NcH or o; R and R are hydrogen or together form a 1,2-benzoradical; and ===indicates an optional double bond. 2. A compound asclaimed in claim 1 where R is lower alkyl. v

3. A compound as claimed in claim 2 where the heterocyclic moiety is2-thiazolinyl, 2-benzimidazolyl or 2-benzoxazolyl.

4. A compound as claimed in claim 3 being the compoundZ-thiazolinylthio(triethylphosphine)gold.

5. A compound as claimed in claim 3 being the compound2-benzimidazolylthio'(triethylphosphine)gold.

6-.A compound as claimed in claim 3 being the compound2-benzoxazolylthio(triethylphosphine)goldi UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION PATENT NO. 3,883,546

DATED May 13, F575 INVENIOR(S) Blaine ii I. Sutton and Joseph Weinstoci:

It is certified that error appears in the above-identified patent andthat sard Letters Patent are hereby corrected as shown below:

Colucm I under structure put "FORMULA I Column 5, line 27 change 7--phine(550161" to read --phine)gold Column 6, lines 52-53 should readZ-benzimidazolylthio- (triphenylphosphite)gold andZ-benzoxazolylthio(triphenylphosphite)gold are obtained-- [SEAL] Arrest:

RUTH C. MASON Arresting Officer Signed and Sealed this C. MARSHALL DANN('rmrmissr'unvr uflare'nrs and Trademarks

1. A COMPOUND OF THE FORMULA:
 2. A compound as claimed in claim 1 whereR1 is lower alkyl.
 3. A compound as claimed in claim 2 where theheterocyclic moiety is 2-thiazolinyl, 2-benzimidazolyl or2-benzoxazolyl.
 4. A compound as claimed in claim 3 being the compound2-thiazolinylthio(triethylphosphine)gold.
 5. A compound as claimed inclaim 3 being the compound 2-benzimidazolylthio(triethylphosphine)gold.6. A compound as claimed in claim 3 being the compound2-benzoxazolylthio(triethylphosphine)gold.